This study aimed to prepare alcohol-free curcumin-loaded zein-propylene glycol alginate (zein-PGA-Cur) nanoparticles using the pH-driven method to enhance the bioavailability and physicochemical stability of curcumin. The prepared zein-PGA-Cur nanoparticles exhibited a small size (360 nm) and negative zeta-potential (-5.8 mV), as well as excellent physical stability, under storage conditions of pH 4.0 and temperature at 4 °C for 30 days. In addition, the Fourier transform infrared spectroscopy results demonstrated that the main interactions of pH-driven for the formation of zein-PGA-Cur nanoparticles were hydrogen bonding, hydrophobic, and electrostatic interactions. Fluorescence spectroscopy revealed that the curcumin-induced fluorescence quenching of zein was static. Circular Dichroism spectroscopy demonstrated that the pH-driven method mainly decreased the β-sheet structure of zein from 3.9 % to 1.4 %. Furthermore, the HT-29 colorectal adenocarcinoma cells viability experiments revealed that the prepared zein-PGA-Cur nanoparticles exhibited excellent biocompatibility. In vivo rat experiments also demonstrated that the prepared nanoparticles resulted in a higher plasma concentration of curcumin, representing a 7.2-fold enhancement in bioavailability compared with pure curcumin crystals. The findings of this study will provide a green and energy-saving method for the development of insoluble drug self-assembly systems and promote their wider applications in drug delivery.